Encourage Patients to Remain Active and Mobile

PD leads to decreased motivation and increased passivity. An active exercise program, even early in the disease, can often avoid this. Furthermore, such a program involves patients in their own care, allows muscle stretching and full range joint mobility, and enhances a better mental attitude toward fighting the disease. By encouraging the patient to take responsibility in fighting the devastations of the disease, the patient becomes an active participant. Physical therapy, which can be...

References

Nobrega F, Glattre E, Kurland LT, Okazaki H. Comments on the epidemiology of parkinsonism including prevalence and incidence statistics for Rochester, Minnesota, 1935-1966. In Brunette JR, Barbeau JR, eds. Progress in Neurogenetics. Amsterdam Excerpta Medica, 1969 474-485. 2. Gudmundsson KR. A clinical survey of parkinsonism in Iceland. Acta Neurol Scand 1967 43(suppl 33) 9-61. 3. Brewis M, Proskanzer DC, Rolland C, Miller H. Neurological diseases in an English city. Acta Neurol Scand 1966...

Th

Where multiple lines were examined, asterisk (*) indicates the lines with pathology. Neurodegeneration or pathology in neurons (N) or Oligodendrocytes (O) are indicated. ( ) Indicates not examined or not reported. Where multiple lines were examined, asterisk (*) indicates the lines with pathology. Neurodegeneration or pathology in neurons (N) or Oligodendrocytes (O) are indicated. ( ) Indicates not examined or not reported. these mice develop weakness related to motor endplate abnormalities and...

Introduction

Parkinson's disease (PD) is a common late-onset, progressive neurodegenerative disease characterized by selective loss of neuronal populations, including dopaminergic (DAergic) neurons of substantia nigra, pars compacta (SNpc), and presence of fibrillar, cytoplasmic inclusions called Lewy bodies (LBs) and Lewy neurites (LNs) (1). While degeneration of dopamine (DA) neurons is responsible for much of the motoric symptoms of PD, neuropathology in PD extends well beyond the DAergic systems (2,3)....

Models Of Ubiquitinproteasome System Dysfunction In Vivo

Pharmacological proteasomal inhibitors have also been used in vivo in an attempt to model UPS dysfunction. Injection of lactacystin in rat SN induced death that was selective for neurons compared to glia. Accumulation of a-synuclein ubiquitin in the form of some rather ill-defined inclusions was noted in the cytosol of nigral neurons (68). Injection of lactacystin or MG132 in rat striatum led to nigrostriatal fiber degeneration, loss of striatal dopamine, and death of nigral dopaminergic...

Transgenic Models Of aSynucleinopathy

With the identification that mutations in a-Syn gene are causative for familial PD, several groups have generated lines of transgenic mice expressing wild type of mutant Hua-Syn under the control of a variety of promoters have been generated (Table 1). In addition, viral vector mediated expression of Hua-Syn has shown Hua-Syn-dependent DAergic neurodegneration. While none of the Hua-Syn transgenic models fully recapitulate all features of PD, a number of these models exhibit significant...

Is Complex I Inhibited Enough

It is still important to determine whether 30 to 40 inhibition of complex I presents significant pathogenic risk. As noted by Davey et al. (95), there are very different thresholds that have to be reached before inhibition of the individual complexes of the ETC result in decreased ATP synthesis in neuronal mitochondria. For example, complexes III and IV need to be inhibited by 80 and 70 , respectively, before ATP synthesis is impacted. In contrast, 25 inhibition of complex I was sufficient to...

Summary

It is widely recognized that mitochondria are a significant source of reactive oxygen species in cells. As many neurodegenerative diseases have oxidative stress as a key phenotype, this leads to the conclusion that altered mitochondrial function could be a critical pathogenic mechanism. This is especially true in PD where it is possible to model the disease using mitochondrial inhibitors and where mitochondrial impairment has been described in PD patients. However, assessing the validity of the...

Genetic Data Supporting A Role For Ubiquitinproteasome System Involvement In Parkinsons Disease

As mentioned, genetic data support the idea that defects in the UPS may lead to PD. Two proteins linked genetically to the disease, PARKIN and UCH-L1, are involved in the UPS. In many cases of early onset autosomal recessive PD affected individuals harbor mutations in the gene encoding for PARKIN. PARKIN has turned out to be an E3 ligase, and mutations in the gene lead to diminution or loss of this activity (reviewed in 3). The subject of PARKIN is discussed extensively elsewhere in this...

Potential Mechanisms for Complex I Inhibition

The concept that complex I inhibition could be a key pathogenic mechanism in PD is supported by the observation that systemic administration of complex I inhibitors results in injury to nigrostriatal dopaminergic neurons and a PD-like syndrome in rodents. This injury occurs as a result of accumulation and concentration of MPP+ in dopaminergic neurons following MPTP administration, which is necessary because MPP+ is not a potent complex I inhibitor (84). However, selective dopaminergic neuron...

Complex I In Parkinsons Disease Evidence And Potential Mechanisms For Impairment

The previous sections establish that complex I is clearly capable of generating ROS under appropriate experimental circumstances, and that excessive ROS generation is most likely to be associated with some level of inhibition of complex I activity. This section of the chapter will describe the mitochondrial impairment that has been reported in PD patients, and will also consider possible mechanisms underlying the impairment. Finally, we will consider whether this level of impairment is...

The Ubiquitinproteasome System

The UPS is one of the main systems of intracellular protein degradation. Although for the purposes of this chapter, we will only address the potential involvement of the UPS in PD and related disorders, it is important to keep in mind that other protein degradation systems, such as the lysosomes, may also play a role in disease pathogenesis. Targets for degradation by the UPS include, but are not limited to, rapidly turning over, misfolded, damaged, or oxidatively modified proteins. In a...

Studies In Human Parkinsons Disease

Ubiquitin within LBs represents polyubiquitinated proteins (47), suggesting that, if there is dysfunction of the UPS in PD and related LB diseases, this should be at the level of the proteasome. A number of studies have directly assessed proteasomal activity in these disorders, using the method of cleavage of synthetic substrates by cell extracts from brain regions of patients and controls. McNaught and Jenner (48) measured enzymatic activities of the proteasome, and found a specific decrease...

ASynuclein Relationship To The Ubiquitinproteasome System

The first gene found to be linked to PD encodes for the presynaptic protein a-synu-clein (23), which turned out to be a major component of Lewy bodies (LBs) (24). Topics related to a-synuclein are reviewed elsewhere in this volume. We will only address here issues related to its possible relationship with the UPS. The first issue is whether a-synuclein is degraded by the UPS and whether it is ubiquitinated. Initial reports (25,26) suggested that a-synuclein is ubiquitinated and degraded by the...

Evidence for Complex I Impairment in Parkinsons Disease

Over the last 15 years there have been a number of reports of diminished complex I activity in tissues obtained from patients with Parkinson's disease. Decreased complex I activity has been reported in substantia nigra and striatum of PD brains, and has also been described in skeletal muscle and platelets (78,79), and such deficits are apparent before the onset of treatment (80). Typically, the reported decrease of complex I activity from these studies is approximately 30 to 40 when corrected...

Conclusions

Mitochondria are clearly an important potential source of ROS in neurons. However, it is critical to understand the mechanisms of ROS generation as well as have a solid appreciation of the methods used to dissect mechanisms. The analysis of mechanisms of ROS generation reveals several potential sources of oxidants, although we would conclude that the most efficacious oxidant-production pathway (succinate-driven reverse electron transport) is unlikely to be of major significance in either intact...

Models Of Ubiquitinproteasome System Dysfunction In Cell Culture

The co-existence of proteasomal dysfunction, at least in the SN, with obvious protein aggregation in the form of LBs raises the chicken and egg dilemma. As demonstrated by Bence et al. (55), protein aggregation can lead to UPS dysfunction. The studies of the effects of purified soluble or fully aggregated a-synuclein mentioned above support this idea. The question that ourselves and others have tried to tackle is whether the converse can also occur that is whether proteasomal dysfunction can...

Complex I Structure Function And Mechanisms Of Ros Generation

NADH-ubiquinone oxidoreductase, or Complex I, (EC 1.5.6.3 ) is the first and the largest complex in the chain of electron transporters of the inner mitochondrial membrane. Its function is to oxidize molecules of NADH produced in the Krebs cycle and to pass the yielded energy in the form of reduced quinone down the redox potential gradient to Complex III along with transferring protons (n 4-5) across the inner membrane. Pumping protons from mitochondrial matrix creates the mitochondrial...

Mechanistic Insights Into aSynucleinopathy From Transgenic Models

Given the wide variety of phenotypes exhibited by the different a-Syn transgenic models, mechanistic conclusions from these models can be difficult for a casual observer. However, closer examinations of the transgenic mouse models do reveal significant mechanistic insights into the in vivo pathogenesis of a-synucleinopathy. The most important implication of various a-Syn transgenic models is that we can conclude that a-Syn abnormalities cause neuronal dysfunction and neurodegeneration in vivo....

Summary of Clinical Phases of Levodopa Therapy

One can usually discern four clinical phases of PD in relation to treatment with levodopa. When levodopa is first introduced, there is a long-duration response from each dose, with few motoric complications. This is the initial period of maximum benefit without adverse motor effects. The duration of this phase varies, but usually lasts two to three years. Phase 2 Motoric Complication Period With continuing treatment, the duration of beneficial response gradually shortens in almost all patients...

Problems with Levodopa Therapy

As PD worsens or with long-term usage of levodopa, more serious and persistent complications, such as wearing off fluctuations and dyskinesias (abnormal involuntary movements) emerge these motor complications affect 75 of patients after six years of levodopa therapy (1). These problems markedly impair the quality of life and functional status of affected patients and prove challenging not only for the patient but also for the treating physician. Today, these motor complications, especially...

ASynuclein Polymerization

PD is characterized neuropathologically by the presence of Lewy bodies and neurites in the substantia nigra (1,61,62). a-Synuclein was first identified as a major protein component of Lewy bodies in both PD and DLB in 1997 (1). Antibodies to a-synuclein, but not - or -synuclein, strongly stain Lewy bodies and neurites, as well as filamentous material isolated from these inclusions (31). The ability of a-synuclein to form fibrils in vitro that are similar to those seen in Lewy bodies (21,63),...

Tau Pathology In Parkinsonian Degeneration

Tau pathology defines several of the parkinsonian neurodegenerative diseases, including CBD, progressive supranuclear palsy (PSP), frontal temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), amylotrophic lateral sclerosis parkinsonism-dementia complex of Guam (ALS PDC Guam) and dementia puglistica. Together, these diseases are referred to as tauopathies a designation that evokes the strong correlative evidence between tau pathology and neurodegeneration in these parkinsonian...

Amylotrophic Lateral Sclerosis Parkinsonism Dementia Complex of Guam

ALS PDC Guam is a progressive neurodegenerative disorder that affects the Chamorro residents of Guam and the Mariana Islands. Clinically, these patients show a combination of motor neuron disease and progressive cognitive dysfunction with extrapyramidal signs. Neuropathologically the disease is characterized by cortical atrophy with abundant neuron loss and widely distributed tau neurofibrillary pathology similar to that observed in AD (12,45). The tau pathology of ALS PDC Guam is similar both...

Index

A-Synuclein chaperones, 177-179 clearance, 177-179 degradation, 177-179 disorder types, 75-76 genetic make up, 76-78 genetics of, 75-79 modifications, 174-176 glycosylation, 175-176 oxidation and nitration, 174-175 phosphorylation, 175-176 molecular biology of, 77-78 PARKIN protein and, 209-210 Parkinson's Disease and, 167-179 polymerization, 172-174 positive cytoplasmic inclusions, 356-357 protein family, 169-172 susceptibility genes and, 161 toxic chemicals, 176-177 transgenic Drosophila...

Evidence For A Genetic Component In Parkinsons Disease

While familial aggregation of PD has been observed for many years (2), it has been widely debated whether it is due to genetic or environmental factors. One indication of genetic causality in a disorder is increased concordance rates in genetically identical monozygotic (MZ) twins compared to nonidentical dizygotic (DZ) twins. Early studies failed to detect differences in concordance rates and concluded that no major genetic factors for PD existed (7,8). Reappraisals of this evidence showed...

Neuropathology Characterization

Ultimately, the neuropathological examination of PARKIN-positive cases may provide the most useful information toward understanding the pathogenic mechanisms in PARKIN-positive PD. The first reports of neuropathology in PARKIN-proven disease revealed a near-complete loss of pigmented dopaminergic neurons of the SNpc, reminiscent of advanced cases of sporadic PD (25). Autopsy of Japanese juvenile-onset PARKIN-positive PD showed that neuronal loss and gliosis were restricted to the SNpc and locus...

Neurochemical Effects of MPTP

PD neurochemical alterations not only involve dopamine, but also other monoami-nergic and nonmonoaminergic systems including acetylcholine and several neuro-peptides (36). Although following MPTP administration, changes in a number of neurotransmitter and neuromodulator systems have also been documented especially in monkeys, the most consistent and significant alterations occur in the dopaminergic systems (21). Overall, it is fair to say that among the different species sensitive to MPTP,...

DJ1 Function

Early evidence suggested the involvement of DJ-1 in cell-cycle regulation and oncogenesis, sperm maturation and fertilization, control of gene transcription, regulation of mRNA stability, and response to cell stress. Initially, a human cDNA termed DJ-1 was identified as a novel oncogene that transformed NIH3T3 cells in cooperation with H-Ras (24). More recent proteomic-based studies found increased expression of the DJ-1 protein in various human tumors, confirming the involvement of DJ-1 in...

Mutation Analysis

Several studies have now been carried out to evaluate the PINK1 mutation burden in PD patients around the world. These data demonstrate that PINK1 mutations account for 5 to 10 of ARPD cases. The emerging phenotype is of early-onset PD (range 18-39 years) lacking major atypical features. This suggests that PINK1 is distinct from parkinsonism associated with PARKIN or DJ-1. While PINK1 is unequivocally associated with young-onset ARPD, it remains difficult to quantify the overall proportion of...

Levodopa Therapy For Parkinsons Disease Historical Introduction

Following the discovery of striatal dopamine deficiency in PD (36,37), Birkmayer and Hornykiewicz (38) injected small doses of levodopa (up to 150 mg) intravenously and reported a transient reversal of akinesia. Levodopa was previously shown by Carlsson et al. (39) to reverse reserpine-induced parkinsonism in rabbits. Barbeau et al. (40) also reported benefit with small oral doses of levodopa (200 mg). Subsequently, many other investigators using small oral or intravenous doses reported similar...

Identification Of Park7idj1

The PARK7 locus was identified as part of a research program Genetic Research in Isolated Populations (GRIP) (17). This study population from the southwest of the Netherlands has been genetically isolated for several centuries. Since 1750, this population has grown with minimal immigration from 150 individuals to an estimated 20,000 descendants, now scattered over eight adjacent villages, suggesting that the genetic background of this population could be more homogeneous than that of the...

Genetics of Parkinsons Disease

Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, Maryland, U.S.A. Alzheimer's Laboratory, Sant Pau Hospital, Barcelona, Spain HEREDITY AND GENETICS IN PARKINSON'S DISEASE Eighty years after James Parkinson wrote his Essay On the Shaking Palsy, Gowers (1) suggested that genetics may play a substantial role in Parkinson's disease (PD), a view shared by Charcot's student Leroux, who stated, A true cause of paralysis agitans, and perhaps the only...

Pink1 And Mitochondrial Dysfunction

Mitochondrial dysfunction has long been associated with PD. Respiratory chain enzyme deficiencies have been widely reported in the substantia nigra of sporadic PD patients (20-22). Complex I is vulnerable to modification by oxidative stress, and when deregulated is a source of free radicals or reactive oxygen species (ROS) (23,24). Mitochondria are the main providers of cellular energy, sustaining aerobic life through the flow of electrons down the electron transport system (ETS). The ETS is...

Applications of the Drosophila aSynuclein Model

The coincidence of neuronal loss and the formation of a-synuclein positive aggregates in a-synuclein-expressing flies prompted several studies of the possible involvement of aggregate formation in dopamine neuron loss. The first study in Drosophila to investigate this matter demonstrated that overexpression of the chaperone, HSP70, abrogated the a-synuclein-induced loss of TH-positive neurons without detectably influencing the appearance of Lewy body-like aggregates (42). Furthermore, feeding...

THE aSynuclein Transgenic Drosophila Model Of Parkinsons Disease Generation and Characterization

The first gene shown to be associated with a heritable form of PD, a-synuclein, was also the first of the PD-related genes to be studied in Drosophila. Although mutations of the a-synuclein gene appear to be an extremely rare cause of PD, the finding that a-synuclein is a component of the Lewy body protein inclusions observed in patients with the sporadic form of the disease implies that this factor is a causative agent in most forms of PD (36,37). Thus, insight gleaned from studies aimed at...

Genomic Organization Of The Tau Gene Gene Structure and Splicing

Genomic Island Images

MAPT is located in chromosome 17q21 and consists of a noncoding exon 0 followed by 14 coding or partially coding exons (Fig. 1A) (30). Intron 13 is always retained in human MAPT transcripts, resulting in a single last exon comprising exon 13, intron 13, exon 14, and containing the 3' untranslated region (3'UTR). Restriction analyses showed that MAPT contains two CpG islands, one associated with the promoter region upstream of exon 0, the other with exon 9 (31). MAPT produces three FIGURE 1 (A)...

Analytical Epidemiology

The study of PD presents special challenges for risk-factor assessment. There is likely a long period of time when neurons are already damaged, but symptoms are not yet apparent. The length of this silent period may vary among individuals. For this reason, it is difficult to estimate the optimal time frame for queries about past exposures. Risk Factors for Parkinson's Disease Interest and results in the search for environmental risk factors associated with the development of PD have increased...

Phosphorylation and Glycosylation

Phosphorylation is a common mechanism for regulating the activity and function of proteins. In AD, phosphorylation of the cytoskeletal protein tau is associated with disease (102), and it is reasonable to suspect that a similar mechanism may be involved with a-synuclein in PD. In vitro, it has been shown that a-synuclein can be phosphorylated at serine 129. In transfected cells, this phosphorylation is insensitive to stimulation of PKC and protein kinase A (PKA), and at steady state the...

Functional Analysis of a Drosophila PINK1 Ortholog

Three recent papers described the effects of perturbation of a Drosophila homolog of the PINK1 gene (79-81). The human PINK1 gene encodes a putative protein kinase that is upregulated in cancer cells by the tumor-suppressor PTEN (82). The presence of a putative mitochondrial targeting sequence in PINK1 coupled with its predominant localization to mitochondria (83,84) strongly suggested that loss-of-function mutations in PINK1 somehow compromise mitochondrial integrity. This prediction is born...

Mutations In Mapt Overview

In 1994, it was demonstrated that the Irish Mo family, presenting with a disorder then referred to as complex (DDPAC), was genetically linked to a region in chromosome 17q21 including MAPT (55). Individual Mo family members presented with a variety of clinical phenotypes, but the combination of FTD and parkinsonism was most commonly observed. The next two years, follow-up linkage studies in families with autosomal dominantly inherited forms of FTD collected from around the world, established...

Levodopa in Patients with a History of Melanoma

Levodopa is an intermediary metabolite in the synthesis of melanin. For this reason, there has been long-standing concern that this medication might potentially promote the growth of melanoma. While melanoma obviously occurs in patients on levodopa therapy, there is no evidence that the incidence differs from that in the general population (96-99), other than that there seems to be a higher risk for melanoma in patients with PD, even without levodopa treatment (100). In studies of patients with...

The Synuclein Protein Family Structure

A-Synuclein is a small, synaptically localized protein that is expressed most abundantly in neurons (10,11). a-Synuclein, which has been mapped to chromosome 4q21 (12), is the major component of pathological inclusions in PD and other a-synucleinopathies (1,13), and mutations in a-synuclein (A53T, A30P, and E46K) or duplications of this gene have been linked to familial forms of PD and DLB (3-5,14). Studies of the toxicity and pathogenesis of a-synuclein have focused on the polymerization of...

Is Levodopa Neurotoxic or Neuroprotective

One of the most controversial questions regarding the treatment of PD is whether levodopa is neurotoxic. The results of many in vitro studies have suggested that levodopa may be injurious to dopaminergic neurons (86,87). These findings have raised concerns that chronic levodopa exposure might hasten disease progression in PD patients. Accordingly, some physicians and patients have opted to defer the use of levodopa for as long as possible (28). Other physicians have continued to use levodopa as...

Matrix

FIGURE 1 Schematic diagram of the mitochondrial ETC. Note the site of complex I inhibition by rotenone and MPP+, electron leakage and ROS production. Abbreviations ADP, adenosine diphosphate ATP, adenosine triphosphate ETC, electron transport chain FAD, flavin adenine dinucleotide FADH2, flavin adenine dinucleotide MPP, 1-methyl-4-phenyl-2,3-dihydropyridinium ion NADH, nico-tinamide dinucleotide ROS, reactive oxygen species TCA, trycarboxylic acid. FIGURE 1 Schematic diagram of the...

Sonic Hedgehog Agonists

The hedgehog family is composed of signaling molecules, including sonic hedgehog is associated with patterning during CNS development. There is also evidence that it promotes survival of dopaminergic neurons, protecting cultures of fetal mid-brain dopaminergic neurons from MPP(+). In the adult brain, Bezard et al. showed that sonic hedgehog is reduced in Parkinson's disease, and its injection inhibits electrical activity in the subthalamic nucleus. (37). Tsuboi and Shults, studying parkinsonian...

Transgenic Mice Using Cell Type Specific Promoters

In addition to using promoters that drive expression of transgenes in a wide variety of neuronal populations, a number of transgenic lines expressing human a-Syn variants using a neuronal cell type specific promoter. Thus far, transgenic mice expressing a-Syn in DAergic neurons and in oligodendrocytes have been reported. First of these mice used a 4.8 kb rat tyrosine hydroxylase (TH) promoter was used to drive high levels of wild type and mutant (A30P and A53T) Hua-Syn expression in DAergic...

Phenotype Of Parkinrelated Parkinsons Disease Clinical Features

The most typical features of Parkinson's disease caused by PARKIN mutations are early-onset typical parkinsonism with a slow clinical course, good or excellent response to low doses of levodopa, frequent treatment-induced dyskinesias and the absence of dementia (47,99). Other frequent signs, that occur in less than 50 of the cases, however, are foot dystonia, brisk reflexes, sleep benefit, and psychiatric or behavioral disorders (Table 1). Two studies (47,90) have compared the frequency of...

Lrrk2 Genetics From Rare Cause To Common Association

The large family from Sagamihara suggested that the PARK8 locus was probably a rare cause of atypical parkinsonism, without the typical Lewy pathology found in sporadic PD (see below). However, groups in other parts of the world were able to find evidence of linkage to the same chromosomal region (8,9), indicating that one gene was likely to be responsible for autosomal dominant disease in several families. The cloning of LRRK2 revealed that there are indeed multiple variants associated with...

Astrocyte Modulation

The calcium binding protein S100B may promote neuronal damage by the activation of various intracellular signaling pathways. Astrocytic activation may increase the production of S100B in the MPTP models of PD, thereby potentiating the neurodegeneration. Arundic acid R - - -2-propyloctanoic acid ONO-2506 is an agent that inhibits S100B synthesis in cultured astrocytes, which has also been shown to reduce delayed ischemic brain damage in models of cerebral ischemia. In an MPTP model of PD, Kato...